Methods and Compositions for Reducing Ischemia-Derived Microvascular Damage

Abstract

Methods of decreasing the extent of occlusion in the lumen of a mammalian blood vessel due to an ischemic or other hypoxic event are provided. In one form, a method includes administering to a patient in need thereof a pharmaceutically effective amount of an inhibitor of δ protein kinase C, either alone or in combination with a second therapeutic agent, and wherein the blood vessel is a blood vessel of the microvasculature. Additionally, methods of decreasing endothelial cell swelling in a mammalian blood vessel due to an ischemic or other hypoxic event are also provided. In one form, a method includes administering to a patient in need thereof a pharmaceutically effective amount of an inhibitor of δ protein kinase C, either alone or in combination with a second therapeutic agent.

1 . A method of decreasing the extent of occlusion in the lumen of a mammalian blood vessel due to an ischemic event, comprising:
 administering to a patient in need thereof a therapeutically effective amount of an inhibitor of δ protein kinase C, wherein said blood vessel is a blood vessel of the microvasculature.   
     
     
         2 . The method of  claim 1 , wherein said inhibitor is a peptide. 
     
     
         3 . The method of  claim 2 , wherein said peptide is δV1-1 having an amino acid sequence set forth in SEQ ID NO:1. 
     
     
         4 . The method of  claim 2 , wherein said peptide is δV1-1 having an amino acid sequence set forth in SEQ ID NO:1, δV1-2 having an amino acid sequence set forth in SEQ ID NO:2, δV1-5 having an amino acid sequence set forth in SEQ ID NO:3, δV5 having an amino acid sequence set forth in SEQ ID NO:4, or a combination thereof. 
     
     
         5 . The method of  claim 2 , wherein said peptide is δV1-1 having an amino acid sequence set forth in SEQ ID NO:1, δV1-2 having an amino acid sequence set forth in SEQ ID NO:2, δV1-5 having an amino acid sequence set forth in SEQ ID NO:3, δV5 having an amino acid sequence set forth in SEQ ID NO:4, a fragment of δV1-1, a fragment of δV1-2, a fragment of δV1-5, a fragment of δV5, a derivative of δV1-1, a derivative of δV1-2, a derivative of δV1-5, a derivative of δV5, or a combination thereof. 
     
     
         6 . The method of  claim 2 , wherein said peptide has an amino acid sequence having at least about 50% identity to the amino acid sequence of δV1-1 set forth in SEQ ID NO:1, at least about 50% identity to the amino acid sequence of δV1-2 set forth in SEQ ID NO:2, at least about 50% identity to the amino acid sequence of δV1-5 set forth in SEQ ID NO:3, or at least about 50% identity to the amino acid sequence of δV5 set forth in SEQ ID NO:4. 
     
     
         7 . The method of  claim 1 , wherein said blood vessel is a capillary, arteriole or venule. 
     
     
         8 . The method of  claim 7 , wherein said capillary has an inner diameter of about 5 μm to about 10 μm. 
     
     
         9 . The method of  claim 1 , wherein said occlusion is further caused by reperfusion-induced injury to said blood vessel. 
     
     
         10  The method of  claim 1 , wherein endothelial swelling contributes to said occlusion. 
     
     
         11 . The method of  claim 1 , wherein said occlusion is caused by blood cells in said blood vessel. 
     
     
         12 . The method of  claim 11 , wherein said blood cells are leukocytes, erythrocytes, or a combination thereof. 
     
     
         13 . The method of  claim 1 , further comprising administering a second therapeutic agent 
     
     
         14 . The method of  claim 13 , wherein said second therapeutic agent is a vasodilator. 
     
     
         15 . The method of  claim 14 , wherein said vasodilator is bradykinin, adenosine, prostacyclin, iloprost, cisaprost; nicotinic acid, niacin, a beta adrenergic blocking drug, or a combination thereof. 
     
     
         16 . A method of decreasing endothelial cell swelling in a mammalian blood vessel due to an ischemic event, comprising:
 administering to a patient in need thereof a therapeutically effective amount of an inhibitor of δ protein kinase C.   
     
     
         17 . The method of  claim 16 , wherein said inhibitor is a peptide. 
     
     
         18 . The method of  claim 16 , wherein said peptide is δV1-1 having an amino acid sequence set forth in SEQ ID NO:1. 
     
     
         19 . The method of  claim 16 , wherein said peptide is δV1-1 having an amino acid sequence set forth in SEQ ID NO:1, δ1-2 having an amino acid sequence set forth in SEQ ID NO:2, δV1-5 having an amino acid sequence set forth in SEQ ID NO:3, δV5 having an amino acid sequence set forth in SEQ ID NO:4, or a combination thereof. 
     
     
         20 . The method of  claim 16 , wherein said peptide is δV1-1 having an amino acid sequence set forth in SEQ ID NO:1, δV1-2 having an amino acid sequence set forth in SEQ ID NO:2, δV1-5 having an amino acid sequence set forth in SEQ ID NO:3, δV5 having an amino acid sequence set forth in SEQ ID NO:4, a fragment of δV1-1, a fragment of δV1-2, a fragment of δV1-5, a fragment of δV5, a derivative of δV1-1, a derivative of δV1-2, a derivative of δV1-5, a derivative of δV5, or a combination thereof. 
     
     
         21 . The method of  claim 16 , wherein said peptide has an amino acid sequence having at least about 50% identity to the amino acid sequence of δV1-1 set forth in SEQ ID NO:1, at least about 50% identity to the amino acid sequence of δV1-2 setforth in SEQ ID NO:2, at least about 50% identity to the amino acid sequence of δV1-5 set forth in SEQ ID NO:3, or at least about 50% identity to the amino acid sequence of δV5 set forth in SEQ ID NO:4. 
     
     
         22 . The method of  claim 16 , wherein said blood vessel is a capillary. 
     
     
         23 . The method of  claim 22 , wherein said capillary has an inner diameter of about 5 μm to about 10 μm. 
     
     
         24 . The method of  claim 14 , further comprising administering a second therapeutic agent. 
     
     
         25 . The method of  claim 24 , wherein said second therapeutic agent is a vasodilator. 
     
     
         26 . The method of  claim 25 , wherein said vasodilator is bradykinin, adenosine, prostacyclin, iloprost, cisaprost; nicotinic acid, niacin, a beta adrenergic blocking drug, or a combination thereof.